Prostate cancer ranges in severity from relatively benign to extremely aggressive. Some prostate cancers are slow growing, causing few clinical symptoms. In these cases, a patient will most often die with prostate cancer rather than from prostate cancer. Aggressive cancers spread rapidly to the lymph nodes, other organs and in particular, bone. Death usually results from aggressive behavior of this form of cancer. Therefore, there is a critical need to identify those individuals at high risk for aggressive disease as this could have a significant impact on the clinical management of prostate cancer. Genetics is believed to play an important role in determining prostate cancer risk and outcome of prostate cancer. Conventional methods such as linkage analysis and gene association study have proved less successful in identifying genes responsible for prostate cancer. We believe that gene expression profiles can be a product of genotype, and the aggressiveness signature genes may arise through a heritable trait or traits that may represent a risk factor for developing more severe form of prostate cancer. Therefore, we hypothesize that variation in gene expression strongly influences tumor behavior and clinical outcome of prostate cancer. The levels of gene expression function as surrogates for genetic markers that can map the gene variants which underlie both the gene-expression changes and tumor aggressiveness. There are three specific aims for this study: 1). To identify and validate a set of signature transcripts that are differentially expressed in non-malignant tissues between patients with more aggressive and patients with less aggressive prostate cancer; 2). To map genetic determinants of these signature transcripts. 3). To characterize selected candidate genes and their roles in aggressive prostate cancer. To accomplish these, we will survey all known human genes for their expression in normal non-malignant tissues of prostate cancer patients. We will evaluate the inherited expression difference between patients with more aggressive cancer and patients with less aggressive cancer and identify a set of signature genes that may be used as genetic markers for prediction of aggressive prostate cancer. We will investigate genetic determinants of these signature genes using single nucleotide polymorphisms as genetic markers and gene expression level as quantitative trait. We will also explore the role of these signature genes in aggressive prostate cancer by performing large scale gene association study. The proposed study will help us identify genetic risk factors and markers responsible for aggressive behavior of prostate cancer. More importantly, characterization of inherited gene expression signature could point to targets for screening, preventive and therapeutic studies. [unreadable] [unreadable] [unreadable]